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The activation of spliced X-box binding protein 1 by isorhynchophylline therapy improves diabetic encephalopathy

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Abstract

The primary symptom of diabetic encephalopathy (DE), a kind of central diabetic neuropathy caused by diabetes mellitus (DM), is cognitive impairment. In addition, the tetracyclic oxindole alkaloid isorhynchophylline (IRN) helps lessen cognitive impairment. However, it is still unclear how IRN affects DM and DE and what mechanisms are involved. The effectiveness of IRN on brain insulin resistance was carefully examined in this work, both in vitro and in vivo. We found that IRN accelerates spliced form of X-box binding protein 1 (sXBP1) translocation into the nucleus under high glucose conditions in vitro. IRN also facilitates the nuclear association of pCREB with sXBP1 and the binding of regulatory subunits of phosphatidylinositol 3-kinase (PI3K) p85α or p85β with XBP1 to restore high glucose impairment. Also, IRN treatment improves high glucose–mediated impairment of insulin signaling, endoplasmic reticulum stress, and pyroptosis/apoptosis by depending on sXBP1 in vitro. In vivo studies suggested that IRN attenuates cognitive impairment, ameliorating peripheral insulin resistance, activating insulin signaling, inactivating activating transcription factor 6 (ATF6) and C/EBP homology protein (CHOP), and mitigating pyroptosis/apoptosis by stimulation of sXBP1 nuclear translocation in the brain. In summary, these data indicate that IRN contributes to maintaining insulin homeostasis by activating sXBP1 in the brain. Thus, IRN is a potent antidiabetic agent as well as an sXBP1 activator that has promising potential for the prevention or treatment of DE.

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Data availability

All data of the present study are available from the corresponding author upon reasonable requests.

Abbreviations

AlCl 3 :

aluminum chloride

AMPA :

alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

ANOVA :

one-way analysis of variance

ASC :

apoptosis-associated speck-like protein containing a caspase recruitment domain

ATF4 :

activating transcription factor 4

ATF6 :

activating transcription factor 6

BBB :

blood-brain barrier

BCL2 :

B-cell lymphoma 2

BDNF :

brain-derived neurotrophic factor

BSA :

bovine serum albumin

C/EBP :

CCAAT/enhancer binding protein

caspase-1 :

cysteinyl aspartate–specific proteinase 1

CCK‐8 :

Cell Counting Kit-8

CHOP :

C/EBP homologous protein

CL :

contacting latency

CNS :

central nervous system

Co-IP :

co-immunoprecipitation

CREB :

cAMP response element binding protein

DAPI :

2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride

DCFH-DA :

2,7-dichlorodihydrofluorescein diacetate

DE :

diabetic encephalopathy

D-gal :

d-galactosamine

DL :

drinking latency

DM :

diabetes mellitus

DMEM :

Dulbecco’s modified Eagle’s medium

DNA :

deoxyribonucleic acid

DNase :

deoxyribonuclease

ECL :

efficient chemiluminescence

EL :

escape latency

ELISA :

enzyme-linked immunosorbent assay

ERAD :

ER-associated degradation

ERS :

endoplasmic reticulum stress

ERSE :

ERS response element

FACS :

fluorescent-activated cell sorting

FBG :

fasting blood glucose

FITC :

fluorescein isothiocyanate

GABA :

gamma-aminobutyric acid

GABRA1 :

gamma-aminobutyric receptor subunit α1

GAP43 :

growth-associated protein 43

GAPDH :

glyceraldehyde-3-phosphate dehydrogenase

GSDMD :

recombinant gasdermin D

HEK :

human embryonic kidney

HEPES :

2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid

HOMA‐IR :

homeostasis model assessment of insulin resistance

i.p. :

intraperitoneally

IL-1β :

interleukin-1 beta

IR :

insulin resistance

IRE1α :

inositol-requiring enzyme 1 alpha

IRN :

isorhynchophylline

IRS1 :

insulin receptor substrate 1

KRP :

Krebs‐Ringer phosphate

m-IL-1β :

mature IL-1β

mRNA :

messenger RNA

MWM :

Morris water maze

N2A :

mouse neuroblastoma N2a cells

2‐NBDG :

2-[N‐(7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl)-amino)-2-deoxy-d-glucose

NLRP3 :

NOD-like receptor protein 3

NRF2 :

nuclear factor erythroid 2–related factor 2

OS :

oxidative stress

PBS :

phosphate buffered saline

pCREB :

phosphorylation of cAMP response element binding protein

pGAP43 :

phosphorylation of growth-associated protein 43

PHAs :

primary hippocampal astrocytes

PI :

propidium iodide

PI3K :

phosphatidylinositol 3-kinase

pTrkB :

phosphorylation of tropomyosin receptor kinase B

PVDF :

polyvinylidene fluoride

ROS :

reactive oxygen species

SA% :

spontaneous alternation percentage

SD :

Sprague Dawley

SDS-PAGE :

sodium dodecyl sulfate-polyacrylamide gel electrophoresis

shRNA :

short hairpin RNA

shXBP1 :

short hairpin RNA of XBP1

SPSS :

Statistical Product and Service Solutions

STZ :

streptozotocin

T1DM :

type 1 diabetes mellitus

TrkB :

tropomyosin receptor kinase B

TUNEL :

terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling

UPR :

unfolded protein response

XBP1 :

X-box binding protein 1

YM :

Y-maze

References

  • Acosta-Alvear D, et al. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell. 2007;27(1):53–66.

    Article  PubMed  CAS  Google Scholar 

  • Akiyama M, et al. X-box binding protein 1 is essential for insulin regulation of pancreatic α-cell function. Diabetes. 2013;62(7):2439–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Albert ML. Death-defying immunity: do apoptotic cells influence antigen processing and presentation? Nat Rev Immunol. 2004;4(3):223–31.

    Article  PubMed  CAS  Google Scholar 

  • Alonso M, Medina JH, Pozzo-Miller L. ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem. 2004;11(2):172–8.

    Article  PubMed  PubMed Central  Google Scholar 

  • Andrisani OM. CREB-mediated transcriptional control. Crit Rev Eukaryot Gene Expr. 1999;9(1):19–32.

    Article  PubMed  CAS  Google Scholar 

  • Bandopadhyay R, de Belleroche J. Pathogenesis of Parkinson’s disease: emerging role of molecular chaperones. Trends Mol Med. 2010;16(1):27–36.

    Article  PubMed  CAS  Google Scholar 

  • Bellezza I, et al. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta, Mol Cell Res. 2018;1865(5):721–33.

    Article  CAS  Google Scholar 

  • Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 2001;292(5521):1552–5.

    Article  PubMed  CAS  Google Scholar 

  • Bergsbaken T, Cookson BT. Macrophage activation redirects yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis. PLoS Pathog. 2007;3(11):09.

    Article  Google Scholar 

  • Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009;7(2):99–109.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Birnbaum Y, et al. Combined SGLT2 and DPP4 inhibition reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic nephropathy in mice with type 2 diabetes. Cardiovasc Drugs Ther. 2018;32(2):135–45.

    Article  PubMed  CAS  Google Scholar 

  • Boden G. Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes. 2011;18(2):139–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cai XJ, Xu HQ, Lu Y. C-peptide and diabetic encephalopathy. Chin Med Sci J. 2011;26(2):119–25.

    Article  PubMed  CAS  Google Scholar 

  • Chen Y, et al. A bacterial invasin induces macrophage apoptosis by binding directly to ICE. EMBO J. 1996;15(15):3853–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Czabotar PE, et al. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014;15(1):49–63.

    Article  PubMed  CAS  Google Scholar 

  • Dey S, et al. Both transcriptional regulation and translational control of ATF4 are central to the integrated stress response. J Biol Chem. 2010;285(43):33165–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Díaz-Gerevini GT, et al. Diabetic encephalopathy: beneficial effects of supplementation with fatty acids ω3 and nordihydroguaiaretic acid in a spontaneous diabetes rat model. Lipids Health Dis. 2019;18(1):43.

    Article  PubMed  PubMed Central  Google Scholar 

  • Fang Y, et al. Pyroptosis: a new frontier in cancer. Biomed Pharmacother. 2020;121:109595.

    Article  PubMed  CAS  Google Scholar 

  • Figurov A, et al. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature. 1996;381(6584):706–9.

    Article  PubMed  CAS  Google Scholar 

  • Fink SL, Cookson BT. Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol. 2006;8(11):1812–25.

    Article  PubMed  CAS  Google Scholar 

  • Fink SL, Bergsbaken T, Cookson BT. Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc Natl Acad Sci USA. 2008;105(11):4312–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012;26(12):1268–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Giordano A, et al. Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. J Lipid Res. 2013;54(9):2423–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Guo Y, et al. Thioredoxin-1 is a target to attenuate Alzheimer-like pathology in diabetic encephalopathy by alleviating endoplasmic reticulum stress and oxidative stress. Front Physiol. 2021;12:651105.

    Article  PubMed  PubMed Central  Google Scholar 

  • He F, Ru X, Wen T. NRF2, a transcription factor for stress response and beyond. Int J Mol Sci. 2020;21(13):4777.

  • Hersh D, et al. The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc Natl Acad Sci USA. 1999;96(5):2396–401.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hetz C, Papa FR. The unfolded protein response and cell fate control. Mol Cell. 2018;69(2):169–81.

    Article  PubMed  CAS  Google Scholar 

  • Hetz C, et al. The unfolded protein response: integrating stress signals through the stress sensor IRE1α. Physiol Rev. 2011;91(4):1219–43.

    Article  PubMed  CAS  Google Scholar 

  • Hillary RF, FitzGerald U. A lifetime of stress: ATF6 in development and homeostasis. J Biomed Sci. 2018;25(1):48.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hu H, et al. The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol. 2018;9:3083.

    Article  PubMed  CAS  Google Scholar 

  • Jiang Y, et al. GLP-1 improves adipocyte insulin sensitivity following induction of endoplasmic reticulum stress. Front Pharmacol. 2018;9:1168.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jin W. Regulation of BDNF-TrkB signaling and potential therapeutic strategies for Parkinson’s disease. J Clin Med. 2020;9(1):257.

  • Jurczak MJ, et al. Dissociation of inositol-requiring enzyme (IRE1α)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice. J Biol Chem. 2012;287(4):2558–67.

    Article  PubMed  CAS  Google Scholar 

  • Kanda N, Watanabe S. 17beta-estradiol inhibits oxidative stress-induced apoptosis in keratinocytes by promoting Bcl-2 expression. J Invest Dermatol. 2003;121(6):1500–9.

    Article  PubMed  CAS  Google Scholar 

  • Kaser A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008;134(5):743–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kawasumi M, et al. Targeted introduction of V642I mutation in amyloid precursor protein gene causes functional abnormality resembling early stage of Alzheimer’s disease in aged mice. Eur J Neurosci. 2004;19(10):2826–38.

    Article  PubMed  Google Scholar 

  • Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7(12):1013–30.

    Article  PubMed  CAS  Google Scholar 

  • Kraeuter AK, Guest PC, Sarnyai Z. The Y-maze for assessment of spatial working and reference memory in mice. Methods Mol Biol. 2019;1916:105–11.

    Article  PubMed  CAS  Google Scholar 

  • Kumar V, et al. Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci. 2005;25(49):11288–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol. 2003;23(21):7448–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee J, et al. p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis. Nat Med. 2011;17(10):1251–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee HM, et al. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 2013;62(1):194–204.

    Article  PubMed  CAS  Google Scholar 

  • Lee H, Baek SH, Lee JH, Kim C, Ko JH, Lee SG, Chinnathambi A, Alharbi SA, Yang WM, Um JY, Sethi G, Ahn KS. Isorhynchophylline, a potent plant alkaloid, induces apoptotic and anti-metastatic effects in human hepatocellular carcinoma cells through the modulation of diverse cell signaling cascades. Int J Mol Sci. 2017;18(5):1095.

  • Lepretti M, Martucciello S, Aceves MAB, Putti R, Lionetti L. Omega-3 fatty acids and insulin resistance: focus on the regulation of mitochondria and endoplasmic reticulum stress. Nutrients. 2018;10(3):350.

  • Li HQ, et al. Isorhynchophylline alleviates learning and memory impairments induced by aluminum chloride in mice. Chin Med. 2018;13:29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li HQ, et al. Isorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: studies in a transgenic mouse model of Alzheimer’s disease. Brain Behav Immun. 2019;82:264–78.

    Article  PubMed  CAS  Google Scholar 

  • Li DX, et al. NLRP3 inflammasome-dependent pyroptosis and apoptosis in hippocampus neurons mediates depressive-like behavior in diabetic mice. Behav Brain Res. 2020;391:112684.

    Article  PubMed  CAS  Google Scholar 

  • Lin Y, et al. Ginsenoside Rb2 improves insulin resistance by inhibiting adipocyte pyroptosis. Adipocyte. 2020a;9(1):302–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lin J, Cheng A, Cheng K, Deng Q, Zhang S, Lan Z, Wang W, Chen J. New insights into the mechanisms of pyroptosis and implications for diabetic kidney disease. Int J Mol Sci. 2020b;21(19):7057.

  • Liu CL, et al. High-content screening identifies inhibitors of the nuclear translocation of ATF6. Int J Mol Med. 2016;37(2):407–14.

    Article  PubMed  CAS  Google Scholar 

  • Lu J, Pang L, Zhang B, Gong Z, Song C. Silencing circANKRD36 inhibits streptozotocin-induced insulin resistance and inflammation in diabetic rats by targeting miR-145 via XBP1. Inflamm Res. 2021;70(6):695–704.

    Article  PubMed  CAS  Google Scholar 

  • Luan B, et al. CREB pathway links PGE2 signaling with macrophage polarization. Proc Natl Acad Sci USA. 2015;112(51):15642–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Luc K, Schramm-Luc A, Guzik TJ, Mikolajczyk TP. Oxidative stress and inflammatory markers in prediabetes and diabetes. J Physiol Pharmacol. 2019;70(6). https://doi.org/10.26402/jpp.2019.6.01

  • Ma YL, et al. Brain-derived neurotrophic factor antisense oligonucleotide impairs memory retention and inhibits long-term potentiation in rats. Neuroscience. 1998;82(4):957–67.

    Article  PubMed  CAS  Google Scholar 

  • Madhusudhan T, et al. Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Nat Commun. 2015;6:6496.

    Article  PubMed  CAS  Google Scholar 

  • Madhusudhan T, et al. Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function. Blood. 2017;130(12):1445–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mamiya T, et al. Enhancement of spatial attention in nociceptin/orphanin FQ receptor-knockout mice. Brain Res. 1998;783(2):236–40.

    Article  PubMed  CAS  Google Scholar 

  • Mariathasan S, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004;430(6996):213–8.

    Article  PubMed  CAS  Google Scholar 

  • Mariathasan S, et al. Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis. J Exp Med. 2005;202(8):1043–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mariathasan S, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440(7081):228–32.

    Article  PubMed  CAS  Google Scholar 

  • Maris M, et al. Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance. Diabetologia. 2012;55(4):1167–78.

    Article  PubMed  CAS  Google Scholar 

  • Martinon F, et al. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010;11(5):411–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Matzinger M, Fischhuber K, Heiss EH. Activation of Nrf2 signaling by natural products-can it alleviate diabetes? Biotechnol Adv. 2018;36(6):1738–67.

    Article  PubMed  CAS  Google Scholar 

  • May P, May E. Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene. 1999;18(53):7621–36.

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin T, et al. Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration. Mol Neurodegener. 2018;13(1):16.

    Article  PubMed  PubMed Central  Google Scholar 

  • McLaughlin T, Siddiqi M, Wang JJ, Zhang SX. Loss of XBP1 leads to early-onset retinal neurodegeneration in a mouse model of type I diabetes. J Clin Med. 2019;8(6):906.

  • Mijnhout GS, et al. Diabetic encephalopathy: a concept in need of a definition. Diabetologia. 2006;49(6):1447–8.

    Article  PubMed  CAS  Google Scholar 

  • Nakanishi K, Sudo T, Morishima N. Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development. J Cell Biol. 2005;169(4):555–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004;11(4):381–9.

    Article  PubMed  CAS  Google Scholar 

  • Ozcan U, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306(5695):457–61.

    Article  PubMed  Google Scholar 

  • Park SW, et al. The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nat Med. 2010;16(4):429–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Raciti GA, et al. Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells. Diabetologia. 2010;53(5):955–65.

    Article  PubMed  CAS  Google Scholar 

  • Ramqvist T, et al. Wild-type p53 induces apoptosis in a Burkitt lymphoma (BL) line that carries mutant p53. Oncogene. 1993;8(6):1495–500.

    PubMed  CAS  Google Scholar 

  • Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the hallmarks of cancer. Cancer Cell. 2018;34(1):21–43.

    Article  PubMed  CAS  Google Scholar 

  • Sage AT, et al. Metabolic syndrome and acute hyperglycemia are associated with endoplasmic reticulum stress in human mononuclear cells. Obesity (Silver Spring). 2012;20(4):748–55.

    Article  PubMed  CAS  Google Scholar 

  • Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013;1833(12):3460–70.

    Article  PubMed  CAS  Google Scholar 

  • Schönthal AH. Endoplasmic reticulum stress: its role in disease and novel prospects for therapy. Scientifica (Cairo). 2012;2012:857516.

    PubMed  Google Scholar 

  • Seo HA, Lee IK. The role of Nrf2: adipocyte differentiation, obesity, and insulin resistance. Oxidative Med Cell Longev. 2013;2013:184598.

    Article  Google Scholar 

  • Sha H, et al. Stressed out about obesity: IRE1α-XBP1 in metabolic disorders. Trends Endocrinol Metab. 2011;22(9):374–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shao D, et al. CHOP mediates XBP1S-induced renal mesangial cell necrosis following high glucose treatment. Eur J Pharmacol. 2015;758:89–96.

    Article  PubMed  CAS  Google Scholar 

  • Shen X, et al. Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans. PLoS Genet. 2005;1(3):e37.

    Article  PubMed  PubMed Central  Google Scholar 

  • Soares JLS, et al. Gain-of-function variants in NLRP1 protect against the development of diabetic kidney disease: NLRP1 inflammasome role in metabolic stress sensing? Clin Immunol. 2018;187:46–9.

    Article  PubMed  CAS  Google Scholar 

  • Soppet D, et al. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell. 1991;65(5):895–903.

    Article  PubMed  CAS  Google Scholar 

  • Stienstra R, et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A. 2011;108(37):15324–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Takatani T, et al. IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation. Sci Rep. 2016;6:28177.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Takechi R, et al. Blood-brain barrier dysfunction precedes cognitive decline and neurodegeneration in diabetic insulin resistant mouse model: an implication for causal link. Front Aging Neurosci. 2017;9:399.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tan Z, et al. ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells. J Neuroinflammation. 2018;15(1):275.

    Article  PubMed  PubMed Central  Google Scholar 

  • Thumbikat P, et al. Mechanisms underlying Mannheimia haemolytica leukotoxin-induced oncosis and apoptosis of bovine alveolar macrophages. Microb Pathog. 2005;38(4):161–72.

    Article  PubMed  CAS  Google Scholar 

  • Wang P, Yan H, Li JC. CREB-mediated Bcl-2 expression in trichosanthin-induced Hela cell apoptosis. Biochem Biophys Res Commun. 2007;363(1):101–5.

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, et al. Endoplasmic reticulum stress-induced neuronal inflammatory response and apoptosis likely plays a key role in the development of diabetic encephalopathy. Oncotarget. 2016;7(48):78455–72.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang L, et al. Knockout of TRPC6 promotes insulin resistance and exacerbates glomerular injury in Akita mice. Kidney Int. 2019;95(2):321–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang C, et al. Diabetic encephalopathy causes the imbalance of neural activities between hippocampal glutamatergic neurons and GABAergic neurons in mice. Brain Res. 2020;1742:146863.

    Article  PubMed  CAS  Google Scholar 

  • Winnay JN, et al. A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response. Nat Med. 2010;16(4):438–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xian YF, et al. Protective effect of isorhynchophylline against β-amyloid-induced neurotoxicity in PC12 cells. Cell Mol Neurobiol. 2012;32(3):353–60.

    Article  PubMed  CAS  Google Scholar 

  • Xian YF, et al. Isorhynchophylline protects PC12 cells against beta-amyloid-induced apoptosis via PI3K/Akt signaling pathway. Evid Based Complement Alternat Med. 2013;2013:163057.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xian YF, et al. Isorhynchophylline improves learning and memory impairments induced by D-galactose in mice. Neurochem Int. 2014a;76:42–9.

    Article  PubMed  CAS  Google Scholar 

  • Xian YF, et al. Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation. J Alzheimers Dis. 2014b;39(2):331–46.

    Article  PubMed  CAS  Google Scholar 

  • Xiang W, et al. CREB down-regulation in the laterodorsal thalamic nucleus deteriorates memory consolidation in rats. Learn Mem. 2019;26(6):182–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xie C, et al. lncRNA GAS5/miR-452-5p reduces oxidative stress and pyroptosis of high-dlucose-stimulated renal tubular cells. Diabetes Metab Syndr Obes. 2019;12:2609–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xiong W, et al. Atorvastatin inhibits endoplasmic reticulum stress through AMPK signaling pathway in atherosclerosis in mice. Exp Ther Med. 2020;19(3):2266–72.

    PubMed  CAS  Google Scholar 

  • Xu J, et al. Advances in the relationship between pyroptosis and diabetic neuropathy. Front Cell Dev Biol. 2021;9:753660.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xue HY, et al. Neuroprotective properties of aucubin in diabetic rats and diabetic encephalopathy rats. Mol Biol Rep. 2012;39(10):9311–8.

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto K, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell. 2007;13(3):365–76.

    Article  PubMed  CAS  Google Scholar 

  • Yang Y, et al. Transcription factor C/EBP homologous protein in health and diseases. Front Immunol. 2017;8:1612.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ye Z, et al. Parecoxib suppresses CHOP and Foxo1 nuclear translocation, but increases GRP78 levels in a rat model of focal ischemia. Neurochem Res. 2013;38(4):686–93.

    Article  PubMed  CAS  Google Scholar 

  • Yoon SB, et al. Developmental competence of bovine early embryos depends on the coupled response between oxidative and endoplasmic reticulum stress. Biol Reprod. 2014;90(5):104.

    Article  PubMed  Google Scholar 

  • Yoshida H, et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107(7):881–91.

    Article  PubMed  CAS  Google Scholar 

  • Zeinivand M, Nahavandi A, Zare M. Deferoxamine regulates neuroinflammation and oxidative stress in rats with diabetes-induced cognitive dysfunction. Inflammopharmacology. 2020;28(2):575–83.

    Article  PubMed  CAS  Google Scholar 

  • Zhai Y, Meng X, Ye T, Xie W, Sun G, Sun X. Inhibiting the NLRP3 inflammasome activation with MCC950 ameliorates diabetic encephalopathy in db/db mice. Molecules. 2018;23(3):522.

  • Zhang Y, et al. Amino acid deprivation induces CREBZF/Zhangfei expression via an AARE-like element in the promoter. Biochem Biophys Res Commun. 2010;391(3):1352–7.

    Article  PubMed  CAS  Google Scholar 

  • Zhang YN, Yang YF, Xu W, Yang XW. The blood-brain barrier permeability of six indole alkaloids from Uncariae Ramulus Cum Uncis in the MDCK-pHaMDR cell monolayer model. Molecules. 2017;22(11):1944.

  • Zhang C, et al. Evidence on integrating pharmacokinetics to find truly therapeutic agent for Alzheimer’s disease: comparative pharmacokinetics and disposition kinetics profiles of stereoisomers isorhynchophylline and thynchophylline in rats. Evid Based Complement Alternat Med. 2019a;2019:4016323.

    PubMed  PubMed Central  Google Scholar 

  • Zhang T, et al. Transcription factor p53 suppresses tumor growth by prompting pyroptosis in non-small-cell lung cancer. Oxidative Med Cell Longev. 2019b;2019:8746895.

    Article  Google Scholar 

  • Zhao Y, et al. The dynamic changes of endoplasmic reticulum stress pathway markers GRP78 and CHOP in the hippocampus of diabetic mice. Brain Res Bull. 2015;111:27–35.

    Article  PubMed  CAS  Google Scholar 

  • Zheng Q, et al. Isorhynchophylline ameliorates paraquat-induced acute kidney injury by attenuating oxidative stress and mitochondrial damage via regulating toll-interacting expression. Toxicol Appl Pharmacol. 2021;420:115521.

    Article  PubMed  CAS  Google Scholar 

  • Zhou JY, Zhou SW. Isorhynchophylline: a plant alkaloid with therapeutic potential for cardiovascular and central nervous system diseases. Fitoterapia. 2012;83(4):617–26.

    Article  PubMed  CAS  Google Scholar 

  • Zhou Y, et al. Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. Nat Med. 2011;17(3):356–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou Z, Su Y, Fa XE. Isorhynchophylline exerts anti-inflammatory and anti-oxidative activities in LPS-stimulated murine alveolar macrophages. Life Sci. 2019;223:137–45.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Prof. Yuqiang Ding for the critical reading of the manuscript. We thank Dr. Haoqi Ni for optimizing the image analysis method and technical supports.

Funding

This study was supported by the Basic Scientific Research Projects of Wenzhou City (Y20180076), the Natural Science Foundation of Zhejiang province (LY21H030012), and the Natural Science Foundation of China (81671042, 81300308).

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Author notes

  1. Jian Wang, Xuebao Wang, Minxue Zhang and Yan Lang contributed equally to this work.

Authors and Affiliations

  1. Department of Laboratory Animal Science, Fudan University, Shanghai, 200032, China

    Jian Wang, Xuebao Wang & Saidan Ding

  2. Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

    Jian Wang, Minxue Zhang, Yan Lang, Baihui Chen, Yongheng Bai & Saidan Ding

  3. Huangshi Love & Health Hospital, Hubei Polytechnic University, Huangshi, 435000, China

    Jian Wang

  4. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China

    Xuebao Wang

  5. School of Information and Engineering, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Yiru Ye

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  1. Jian Wang
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Contributions

Saidan Ding substantially contributed to the study conception and design, data interpretation, and manuscript revision. Jian Wang and Xuebao Wang performed all the in vitro assays and data analysis. Yongheng Bai, Yiru Ye, and Baihui Chen performed the in vivo experiments and data analysis. Yan Lang and Minxue Zhang contributed to the manuscript preparation. All the authors contributed to the manuscript revision and read and approved the final article.

Corresponding author

Correspondence to Saidan Ding.

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The study was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University. The study was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University.

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Supplementary Information

Fig. S1

insulin-resistant PHAs and insulin-resistant CTX TNA2 cells are successfully established. (a,b) 2-NBDG uptake assay of PHAs (a) and CTX TNA2 cells (b) stimulated with 100 nM insulin for 30 min in preincubation of various concentrations of glucose (20, 40 or 80 mM ) for 24hr by using a fluorometric plate reader. Data are shown as mean ± SD.* P <0.05, ** P <0.01. ns, nonsignificant. (JPG 80 kb)

Fig. S2

2-NBDG uptake assay of PHAs. (a) PHAs were stimulated with 100 nM insulin for 30 min in pretreatment of various concentrations of IRN (1, 10 or 50μM) for 12h after preincubation of 40 mM glucose for 24hr. 2-NBDG uptake assay of PHAs by using a fluorescence microscope. (PNG 211 kb)

High Resolution Image (TIF 1694 kb)

Fig. S3

IRN increases glucose uptake in insulin-resistant CTX TNA2 cells. (a) 2-NBDG uptake assay of CTX TNA2 cells stimulated with 100nM insulin for 30 min in pretreatment of various concentrations of IRN (1, 10 or 50μM) for 12hr after preincubation of 40 mM glucose for 24hr by using a fluorometric plate reader. Data are shown as mean ± SD.* P <0.05, ** P <0.01. ns, nonsignificant. (JPG 80 kb)

Fig. S4

IRN promotes sXBP1 nuclear translocation in insulin-resistant astrocytes. (a) CTX TNA2 cells were treated with IRN (10μM) for 12h after preincubation of 40 mM glucose for 24hr. Immunoblot analysis of total/nuclear/cytoplasmic lysates of CTX TNA2 cells using anti-sXBP1/GAPDH/laminB1 antibodies and subsequent quantification (b). Data are shown as mean ± SD. * P <0.05, ** P <0.01. ns, nonsignificant. (JPG 161 kb)

Fig. S5

The expression of XBP1 and sXBP1 nuclear translocation are decreased after shXBP1 knockdown in PHAs. (a,b) Immunoblot analysis of total/nuclear lysates of PHAs after shXBP1 infection using anti‐sXBP1/ GAPDH/laminB1 antibodies (a) and subsequent densitometry (b). Data are shown as mean ± SD.* P <0.05, ** P <0.01. ns, nonsignificant. (JPG 108 kb)

Fig. S6

The expression of XBP1 and sXBP1 nuclear translocation are decreased after shXBP1 knockdown in CTX TNA2 cells. (a,b) Immunoblot analysis of total/nuclear lysates of CTX TNA2 cells after shXBP1 infection using anti‐sXBP1/ GAPDH/laminB1 antibodies (a) and subsequent densitometry (b). Data are shown as mean ± SD.* P <0.05, ** P <0.01. ns, nonsignificant. (JPG 115 kb)

Fig. S7

The expression of XBP1 and sXBP1 nuclear translocation are increased after XBP1 overexpression in PHAs. (a,b) Immunoblot analysis of total/nuclear lysates of PHAs after XBP1 infection using anti‐sXBP1/ GAPDH/laminB1 antibodies (a) and subsequent densitometry (b). Data are shown as mean ± SD.* P <0.05, ** P <0.01. ns, nonsignificant. (JPG 113 kb)

Fig. S8

IRN activates insulin signaling via XBP1 activation in insulin-resistant astrocytes. (a) PHAs with or without transfection of XBP1 shRNA were stimulated with 100 nM insulin for 30 min in pretreatment of 50μM IRN for 12h after preincubation of 40 mM glucose for 24hr. 2-NBDG uptake assay of PHAs by using a fluorometric plate reader. (b) Immunoblot analysis of lysates of PHAs using anti-pInsR-Tyr1361/InsR/pIRS1-Tyr896/ pIRS1-Ser312/IRS1 antibodies and subsequent densitometry (c). (d) PHAs with or without transfection of XBP1 construct, were stimulated with 100 nM insulin for 30 min in pretreatment of 50μM IRN for 12h after preincubation of 40 mM glucose for 24hr. Immunoblot analysis of lysates of PHAs using anti-pInsR-Tyr1361/InsR/pIRS1-Tyr896/pIRS1-Ser312/IRS1 antibodies and subsequent densitometry (e). (f) CTX TNA2 cells with or without transfection of XBP1 shRNA, were stimulated with 100 nM insulin for 30 min in pretreatment of 50μM IRN for 12h after preincubation of 40 mM glucose for 24hr. 2-NBDG uptake assay of CTX TNA2 cells by using a fluorometric plate reader. Data are shown as mean ± SD.* P <0.05, ** P <0.01. ns, nonsignificant. (JPG 150 kb)

Fig. S9

IRN accelerates CREB-sensitive gene transcription via sXBP1 in insulin-resistant PHAs. (a) PHAs with cotransfection of a luciferase reporter construct driven by CREB and a shRNA construct against XBP1, were stimulated with 100 nM insulin for 30 min in pretreatment of 50μM IRN for 12h after preincubation of 40 mM glucose for 24hr. Assay for CREB transcriptional activation of PHAs via the luminometry. Data are shown as mean ± SD. * P <0.05, ** P <0.01. ns, nonsignificant. (PNG 145 kb)

High Resolution Image (TIF 5066 kb)

Fig. S10

Analyses of production of reactive oxygen species (ROS). (a,b) Flow cytometric analyses of production of ROS of PHAs (a) and relative median fluorescence intensity (MFI) (b). (JPG 45 kb)

Fig. S11

Analyses of apoptosis of N2A cells. (a,b) Flow cytometric analyses of apoptosis of N2A cells (a) and relative MFI (b). (JPG 48 kb)

Fig. S12

IRN increases p85β -sXBP1 interaction in brain in STZ-induced diabetic mice. (a) STZ-induced diabetic mice were intraperitoneally treated with various concentrations of IRN (20,40 or 80mg/kg) or 40mg/kg IRN for 6 weeks. Immunoblot analysis of p85β/sXBP1 proteins in hippocampal lysates immunoprecipitated with anti- p85β antibody. (JPG 74 kb)

Fig. S13

The expression of XBP1 and sXBP1 nuclear translocation are decreased after shXBP1 knockdown in brain in STZ-induced diabetic mice. (a) Immunoblot analysis of total/nuclear lysates of brain of WT mice or diabetic mice after shXBP1 infection using anti‐sXBP1/ GAPDH/laminB1 antibodies (a) and subsequent densitometry (b). Data are shown as mean ± SD. * P <.05, ** P <.01. ns, nonsignificant. WT, wild type. (JPG 63 kb)

Fig. S14

IRN protects against ERS in STZ-induced diabetic mice. (a) STZ-induced diabetic mice were intraperitoneally treated with IRN (40 mg/kg) for 6 weeks. Immunoblot analysis of total/nuclear hippocampal lysates using anti-ATF6/CHOP/laminB1/GAPDH antibodies and subsequent quantification (b). Data are shown as mean ± SD. * P <0.05, ** P <0.01. ns, nonsignificant. (JPG 299 kb)

Fig. S15

IRN attenuates insulin resistance via sXBP1 in brain in STZ-induced diabetic mice. (a-c) STZ-induced diabetic mice with or without intracerebroventricular XBP1 shRNA transfection for 24hr were intraperitoneally treated with various concentrations of IRN (20, 40 or 80mg/kg) or 40mg/kg IRN for 6 weeks. Assay for fasting plasma insulin levels (FINS, a) and fasting plasma insulin levels (FBG, b) in each group. (c) HOMA -IR was calculated from fasting glucose and insulin levels in panels (a) and (b). Data are shown as mean ± SD. * P <0.05, ** P <0.01. ns, nonsignificant. (JPG 86 kb)

Fig. S16

IRN attenuates cognitive impairment and insulin resistance in db/db mice. (a-d) db/db mice were intraperitoneally injected with various concentrations of IRN (20,40 or 80mg/kg) or curcumin (50mg/kg) for 6 weeks. Morris water maze in each group. Representative moving patterns in the probe trials (a). Quantification of the spent time of platform (b). Quantification of the average speed (c). YM in each group. Quantification of spontaneous alternation percentage (SA%) (d). (e-g) Assay for fasting plasma insulin levels (FINS, e) and fasting blood glucose levels (FBG, f) in each group. (g) HOMA -IR was calculated from fasting glucose and insulin levels in panels (e) and (f). Data are shown as mean ± SD. * P <0.05, ** P <0.01. ns, nonsignificant. (PNG 1571 kb)

High Resolution Image (TIF 2292 kb)

Fig. S17

IRN increases sXBP1 nuclear translocation in brain in db/db mice. (a) db/db mice were intraperitoneally treated with various concentrations of IRN (20,40 or 80mg/kg) for 6 weeks. Immunoblot analysis of total/nuclear hippocampal lysates using anti-sXBP1/pIRE1α/IRE1α/laminB1/GAPDH antibodies (a) and subsequent densitometry (b). Data are shown as mean ± SD. * P <0.05, ** P <0.01. ns, nonsignificant. (JPG 77 kb)

Fig. S18

Graphical abstract. IRN attenuates cognitive impairment, ameliorating peripheral insulin resistance, activating insulin signaling, inhibiting ERS, and mitigating pyroptosis/apoptosis by depending on sXBP1 activation in diabetic encephalopathy. (JPG 559 kb)

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Wang, J., Wang, X., Zhang, M. et al. The activation of spliced X-box binding protein 1 by isorhynchophylline therapy improves diabetic encephalopathy. Cell Biol Toxicol 39, 2587–2613 (2023). https://doi.org/10.1007/s10565-022-09789-z

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